Clinical Research Regulation: FDA vs. ICH
On May 9th, 1997, the US Food and Drug Administration (FDA) published in the FEDERAL REGISTER (vol. 62, No 90), the latest rendition of the International Conference on Harmonization (ICH) Guideline covering the conduct of clinical research studies in the seven member nations. Guidelines represent the agency's current thinking on Good Clinical Practices, but do not bind the FDA or the public. However, most clinical research studies are now being conducted in compliance with this guideline, especially if the results might be used for an international regulatory submission. Here are the major differences.
Note: The bolded titles are to ease reading and are not part of the guideline. I'm summarized here, so consult the guideline for exact wording. Also, I've picked only the most notable examples. This is not a complete list.
Notification to Primary Care Physician
ICH recommends that a clinical trial investigator inform a subject's primary physician, if the subject agrees, about the subject's study participation (section 4.3.3) . FDA does not mention such a notice.
ICH requires that the clinical investigator provide the Institutional Review Board (IRB) with a copy of the Investigator Brochure (4.4.2). FDA only requires that the pharmaceutical company sponsor provide it to the investigator; however, many clinical trial sponsors require documentation of receipt from the investigator's IRB (312.55a).
ICH requires a statement from the Institutional Review Board (IRB) that it is organized and operates according to Good Clinical Practices (5.11.1b). FDA does not require clinical research sponsors to obtain such a statement.
Documentation of Protocol Deviations
ICH requires that the investigator document and explain any deviation from the study protocol (4.5.3). FDA does not address this issue.
ICH requires that the clinical investigator maintain records that document adequately that the subjects were provided the doses specified by the protocol AND RECONCILE all investigational products received from the sponsor. FDA requires only the return of unused supplies and does not specify who is responsible for reconciliation (312.62).
ICH prohibits the pharmaceutical company sponsor (or the Contract Research Organization if the responsibility was properly transferred) from providing study medication until all required documentation from the IRB has been obtained (5.14.2). FDA does not address this; however, most sponsors have internal procedures covering this.
The elements differ between ICH (4.8.10) and FDA (50.25a, 50.25b).
ICH requires that the subject receive a SIGNED and DATED copy of the written informed consent (4.8.11). FDA requires that a copy be given to the subject but does not state that it must be a SIGNED copy (50.27).
ICH requires that the clinical investigator make ALL clinical trial-related records available for direct access by the Clinical Research Associate, auditor, IRB, or regulatory agency (4.9.7) and that financial aspects of the trial be in the investigator's files (8.2.4). FDA currently does not require financial records, nor mandate "direct access" (312.62).
ICH requires that the sponsor and clinical investigator sign the study protocol (5.6.3). FDA doesn't have this requirement; however, most sponsors require signatures.
ICH requires that the sponsor provide insurance or indemnify the investigator against claims arising from the trial (5.8.1). FDA does not have such a policy; however, most investigators request and obtain it from the pharmaceutical company or Contract Research Organization.
Case Report Form Changes
ICH requires the monitor (Clinical Research Associate or CRA) ensure that changes/additions/deletions to the case report form (CRF) are made, dated, explained (if necessary), and initialled BY THE INVESTIGATOR or an authorized member of the investigator's staff, such as the Study Coordinator. This authorization must be documented (5.18.4n). FDA does not require documentation of authorization to initial CRF changes.
ICH requires the sponsor document management review and follow-up of the monitoring report as prepared by the Clinical Research Associate (5.18.6d). FDA does not require sponsors to document review of the Clinical Research Associate's monitoring report.
ICH requires a copy of the Clinical Research Associate's Study Initiation Monitoring Report be stored in the investigator's files (8.2.20). This is not required by FDA at this time.
ICH puts responsibility for ensuring that all study documents are on file at the investigational site on the Clinical Research Associate and requires that the Clinical Research Associate confirm that all necessary documents are at the site prior to closing the site (8). FDA holds the investigator responsible for the accuracy and completeness of the records related to the clinical trial.
ICH requires curriculum vitae of both the principal investigator and any sub-investigators (8.2.10). FDA does not require sub-investigator CV's, albeit this is typically a sponsor requirement.
ICH requires a SIGNATURE SHEET to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs in both investigator and sponsor files (8.3.24). FDA does not require documentation of investigator/staff signatures; however, this is typically a sponsor requirement.